Template-Assisted Plasmonic Nanogap Shells for Highly Enhanced Detection of Cancer Biomarkers

We present a template-assisted method for synthesizing nanogap shell structures for biomolecular detections based on surface-enhanced Raman scattering. The interior nanogap-containing a silver shell structure, referred to as a silver nanogap shell (Ag NGS), was fabricated on silver nanoparticles (Ag NPs)-coated silica, by adsorbing small aromatic thiol molecules on the Ag NPs. The Ag NGSs showed a high enhancement factor and good signal uniformity, using 785-nm excitation. We performed in vitro immunoassays using a prostate-specific antigen as a model cancer biomarker with a detection limit of 2 pg/mL. To demonstrate the versatility of Ag NGS nanoprobes, extracellular duplex surface-enhanced Raman scattering (SERS) imaging was also performed to evaluate the co-expression of cancer biomarkers, human epidermal growth factor-2 (HER2) and epidermal growth factor receptor (EGFR), in a non-small cell lung cancer cell line (H522). Developing highly sensitive Ag NGS nanoprobes that enable multiplex biomolecular detection and imaging can open up new possibilities for point-of-care diagnostics and provide appropriate treatment options and prognosis.     

Combining Radiation- with Immunotherapy in Prostate Cancer: Influence of Radiation on T Cells

Radiation of tumor cells can lead to the selection and outgrowth of tumor escape variants. As radioresistant tumor cells are still sensitive to retargeting of T cells, it appears promising to combine radio- with immunotherapy keeping in mind that the radiation of tumors favors the local conditions for immunotherapy. However, radiation of solid tumors will not only hit the tumor cells but also the infiltrated immune cells. Therefore, we wanted to learn how radiation influences the functionality of T cells with respect to retargeting to tumor cells via a conventional bispecific T cell engager (BiTE) and our previously described modular BiTE format UNImAb. T cells were irradiated between 2 and 50 Gy. Low dose radiation of T cells up to about 20 Gy caused an increased release of the cytokines IL-2, TNF and interferon-γ and an improved capability to kill target cells. Although radiation with 50 Gy strongly reduced the function of the T cells, it did not completely abrogate the functionality of the T cells.     

Peptide Modification Diminishes HLA Class II-restricted CD4+ T Cell Recognition of Prostate Cancer Cells

Prostate cancer poses an ongoing problem in the western world accounting for significant morbidity and mortality in the male population. Current therapy options are effective in treating most prostate cancer patients, but a significant number of patients progress beyond a manageable disease. For these patients, immunotherapy has emerged as a real option in the treatment of the late-stage metastatic disease. Unfortunately, even the most successful immunotherapy strategies have only led to a four-month increase in survival. One issue responsible for the shortcomings in cancer immunotherapy is the inability to stimulate helper CD4⁺ T cells via the HLA class II pathway to generate a potent antitumor response. Obstacles to proper HLA class II stimulation in prostate cancer vaccine design include the lack of detectable class II proteins in prostate tumors and the absence of defined class II specific prostate tumor antigens. Here, for the first time, we show that the insertion of a lysosomal thiol reductase (GILT) into prostate cancer cells directly enhances HLA class II antigen processing and results in increased CD4⁺ T cell activation by prostate cancer cells. We also show that GILT insertion does not alter the expression of prostate-specific membrane antigen (PSMA), an important target in prostate cancer vaccine strategies. Our study suggests that GILT expression enhances the presentation of the immunodominant PSMA₄₅₉ epitope via the HLA class II pathway. Biochemical analysis showed that the PSMA₄₅₉ peptide was cysteinylated under a normal physiologic concentration of cystine, and this cysteinylated form of PSMA₄₅₉ inhibited T cell activation. Taken together, these results suggest that GILT has the potential to increase HLA class II Ag presentation and CD4⁺ T cell recognition of prostate cancer cells, and GILT-expressing prostate cancer cells could be used in designing cell therapy and/or vaccines against prostate cancer.     

Evaluation of the PSMA-Binding Ligand 212Pb-NG001 in Multicellular Tumour Spheroid and Mouse Models of Prostate Cancer

Radioligand therapy targeting the prostate-specific membrane antigen (PSMA) is rapidly evolving as a promising treatment for metastatic castration-resistant prostate cancer. The PSMA-targeting ligand p-SCN-Bn-TCMC-PSMA (NG001) labelled with ²¹²Pb efficiently targets PSMA-positive cells in vitro and in vivo. The aim of this preclinical study was to evaluate the therapeutic potential of ²¹²Pb-NG001 in multicellular tumour spheroid and mouse models of prostate cancer. The cytotoxic effect of ²¹²Pb-NG001 was tested in human prostate C4-2 spheroids. Biodistribution at various time points and therapeutic effects of different activities of the radioligand were investigated in male athymic nude mice bearing C4-2 tumours, while long-term toxicity was studied in immunocompetent BALB/c mice. The radioligand induced a selective cytotoxic effect in spheroids at activity concentrations of 3–10 kBq/mL. In mice, the radioligand accumulated rapidly in tumours and was retained over 24 h, while it rapidly cleared from nontargeted tissues. Treatment with 0.25, 0.30 or 0.40 MBq of ²¹²Pb-NG001 significantly inhibited tumour growth and improved median survival with therapeutic indexes of 1.5, 2.3 and 2.7, respectively. In BALB/c mice, no signs of long-term radiation toxicity were observed at activities of 0.05 and 0.33 MBq. The obtained results warrant clinical studies to evaluate the biodistribution, therapeutic efficacy and toxicity of ²¹²Pb-NG001.     

Comparative Evaluation of Urinary PCA3 and TMPRSS2: ERG Scores and Serum PHI in Predicting Prostate Cancer Aggressiveness

It has been suggested that urinary PCA3 and TMPRSS2:ERG fusion tests and serum PHI correlate to cancer aggressiveness-related pathological criteria at prostatectomy. To evaluate and compare their ability in predicting prostate cancer aggressiveness, PHI and urinary PCA3 and TMPRSS2:ERG (T2) scores were assessed in 154 patients who underwent radical prostatectomy for biopsy-proven prostate cancer. Univariate and multivariate analyses using logistic regression and decision curve analyses were performed. All three markers were predictors of a tumor volume ≥0.5 mL. Only PHI predicted Gleason score ≥7. T2 score and PHI were both independent predictors of extracapsular extension (≥pT3), while multifocality was only predicted by PCA3 score. Moreover, when compared to a base model (age, digital rectal examination, serum PSA, and Gleason sum at biopsy), the addition of both PCA3 score and PHI to the base model induced a significant increase (+12%) when predicting tumor volume >0.5 mL. PHI and urinary PCA3 and T2 scores can be considered as complementary predictors of cancer aggressiveness at prostatectomy.     

混炼工艺对炭黑/氯丁橡胶/顺丁橡胶复合材料性能的影响

以氯丁橡胶(CR)/顺丁橡胶(BR)并用胶为基体材料、炭黑为补强填料制备炭黑/CR/BR复合材料,探讨混炼工艺对复合材料性能的影响。结果表明:薄通5次时配合剂在CR/BR并用胶中分散良好;采用先将炭黑混入BR相中再与CR共混的混炼工艺可以提高炭黑的分散性,且炭黑/CR/BR复合材料的硫化特性和物理性能较好。     

玄武岩纤维对NR/SBR并用胶性能的影响

研究玄武岩纤维用量对天然橡胶/丁苯橡胶并用胶硫化特性、物理性能和动态力学性能的影响。结果表明:玄武岩纤维能够明显缩短并用胶的焦烧时间和正硫化时间;当玄武岩纤维用量小于10份时,无机填料分散性较好,并用胶综合物理性能变化较小;当玄武岩纤维用量大于10份时,各项物理性能下降明显;增大玄武岩纤维用量,并用胶的Payne效应增强,加工性能下降。     

硫黄硫化体系对IIR/EPDM共混胶力学性能的影响

研究IIR/EPDM体系中共混比、硫黄硫化体系对其共混胶性能的影响。结果表明 ,IIR与EPDM共混相容性较好 ,可以达到共硫化 ;IIR/EPDM共混比为 75 /2 5时共混胶性能最好 ;用传统硫化体系 (CV)、有效硫化体系 (EV)和半有效硫化体系 (SEV)都能得到性能较好的共混胶 ,其中以CV体系的硫化胶性能最好。     

Environmental Phenol and Paraben Exposure Risks and Their Potential Influence on the Gene Expression Involved in the Prognosis of Prostate Cancer

Prostate cancer (PCa) is one of the leading malignant tumors in US men. The lack of understanding of the molecular pathology on the risk of food supply chain exposures of environmental phenol (EP) and paraben (PB) chemicals limits the prevention, diagnosis, and treatment options. This research aims to utilize a risk assessment approach to demonstrate the association of EP and PB exposures detected in the urine samples along with PCa in US men (NHANES data 2005–2015). Further, we employ integrated bioinformatics to examine how EP and PB exposure influences the molecular pathways associated with the progression of PCa. The odds ratio, multiple regression model, and Pearson coefficients were used to evaluate goodness-of-fit analyses. The results demonstrated associations of EPs, PBs, and their metabolites, qualitative and quantitative variables, with PCa. The genes responsive to EP and PB exposures were identified using the Comparative Toxicogenomic Database (CTD). DAVID.6.8, GO, and KEGG enrichment analyses were used to delineate their roles in prostate carcinogenesis. The plug-in CytoHubba and MCODE completed identification of the hub genes in Cytoscape software for their roles in the PCa prognosis. It was then validated by using the UALCAN database by evaluating the expression levels and predictive values of the identified hub genes in prostate cancer prognosis using TCGA data. We demonstrate a significant association of higher levels of EPs and PBs in the urine samples, categorical and numerical confounders, with self-reported PCa cases. The higher expression levels of the hub genes (BUB1B, TOP2A, UBE2C, RRM2, and CENPF) in the aggressive stages (Gleason score > 8) of PCa tissues indicate their potential role(s) in the carcinogenic pathways. Our results present an innovative approach to extrapolate and validate hub genes responsive to the EPs and PBs, which may contribute to the severity of the disease prognosis, especially in the older population of US men.     

白炭黑与溶聚丁苯橡胶的键接位置对白炭黑/炭黑/溶聚丁苯橡胶复合材料性能的影响

研究白炭黑/炭黑填充星形溶聚丁苯橡胶(SSBR)和分子链自由末端用硅氧烷基团封端改性星形SSBR(S-SSBR)的物理性能、动态力学性能和微观结构。结果表明:随着偶联剂用量(硅氧烷基团物质的量)的增大,星形SSBR复合材料的拉伸强度先增大后减小,S-SSBR复合材料的拉伸强度先减小后增大;星形SSBR和S-SSBR复合材料的300%定伸应力呈增大趋势,压缩疲劳温升降低,0℃下损耗因子(tanδ)增大,60℃下tanδ值减小。当复合材料中硅氧烷基团的物质的量相同时,与星形SSBR复合材料相比,S-SSBR复合材料定伸应力和0℃下tanδ值的增幅、压缩疲劳温升和60℃下tanδ值的降幅较大,填料的分散性较好。     

The Influence of Angiotensin Peptides on Survival and Motility of Human High-Grade Serous Ovarian Cancer Cells in Serum Starvation Conditions

High-grade serous ovarian carcinoma (HGSOC) is the most frequent and malignant form of ovarian cancer. A local renin–angiotensin system (RAS) has been found in the ovary, and changes in selected components of this system were observed in pathological states and also in ovarian cancer. In the present study, we examined the effect of three peptides, Ang-(1-7), Ang-(1-9) and Ang-(3-7), on proliferation and motility of the OVPA8 cell line, a new well-defined and preclinical model of HGSOC. We confirmed the presence of mRNA for all angiotensin receptors in the tested cells. Furthermore, our findings indicate that all tested angiotensin peptides increased the metabolic serum in the medium by activation of cell defense mechanisms such as nuclear factor kappaB signaling pathway andapoptosis. Moreover, tested angiotensin peptides intensified serum starvation-induced cell cycle arrest at the G0/G1 phase. In the case of Ang-(3-7), a significant decrease in the number of Ki67 positive cells (Ki67+) and reduced percentage of activated ERK1/2 levels in ovarian cancer cells were additionally reported. The angiotensin-induced effect of the accumulation of cells in the G0/G1 phase was not observed in OVPA8 cells growing on the medium with 10% FBS. Moreover, in the case of Ang-(3-7), the tendency was quite the opposite. Ang-(1-7) but not Ang-(1-9) or Ang-(3-7) increased the mobility of reluctant-to-migrate OVAP8 cells cultured in the serum-free medium. In any cases, the changes in the expression of VIM and HIF1A gene, associated with epithelial–mesenchymal transition (EMT), were not observed. In conclusion, we speculate that the adaptation to starvation in nutrient-deprived tumors can be modulated by peptides from the renin–angiotensin system. The influence of angiotensin peptides on cancer cells is highly dependent on the availability of growth factors and nutrients.     

Influence of Preoperative Serum Aspartate Aminotransferase (AST) Level on the Prognosis of Patients with Non-Small Cell Lung Cancer

The purpose of this work is to analyze preoperative serum aspartate aminotransferase (AST) levels and their effect on the prognosis of patients with non-small cell lung cancer (NSCLC) after surgical operation. These analyses were performed retrospectively in patients with NSCLC followed by surgery; participants were recruited between January 2004 and January 2008. All clinical information and laboratory results were collected from medical records. We explored the association between preoperative serum AST and recurrence-free survival (RFS), and the overall survival (OS) of NSCLC patients. Kaplan–Meier analysis and Cox multivariate analysis, stratified by the AST median value, were used to evaluate the prognostic effect. A chi-squared test was performed to compare clinical characteristics in different subgroups. A p-value of ≤0.05 was considered to be statistically significant. A total of 231 patients were enrolled. The median RFS and OS were 22 and 59 months, respectively. The AST levels were divided into two groups, using a cut-off value of 19 U/L: High AST (>19 U/L), n = 113 vs. low AST (≤19 U/L), n = 118. Multivariate analysis indicated that preoperative serum AST > 19 U/L (hazard ratio (HR) = 0.685, 95% confidence interval (CI): 0.493–0.994, p = 0.046 for RFS, HR = 0.646, 95% CI: 0.438–0.954, p = 0.028 for OS) was an independent prognostic factor for both RFS and OS. High preoperative serum AST levels may serve as a valuable marker to predict the prognosis of NSCLC after operation.     

UHPLC-ESI-MS/MS Quantification of Relevant Substrates and Metabolites of the Kynurenine Pathway Present in Serum and Peritoneal Fluid from Gastric Cancer Patients—Method Development and Validation

Metabolites and enzymes involved in the kynurenine pathway (KP) are highly promising targets for cancer treatment, including gastrointestinal tract diseases. Thus, accurate quantification of these compounds in body fluids becomes increasingly important. The aim of this study was the development and validation of the UHPLC-ESI-MS/MS methods for targeted quantification of biologically important KP substrates (tryptophan and nicotinamide) and metabolites(kynurenines) in samples of serum and peritoneal fluid from gastric cancer patients. The serum samples were simply pretreated with trichloroacetic acid to precipitate proteins. The peritoneal fluid was purified by solid-phase extraction before analysis. Validation was carried out for both matrices independently. Analysis of the samples from gastric cancer patients showed different accumulations of tryptophan and its metabolites in different biofluids of the same patient. The protocols will be used for the evaluation of tryptophan and kynurenines in blood and peritoneal fluid to determine correlation with the clinicopathological status of gastric cancer or the disease’s prognosis.     

炭黑CD2109对NR/BR胶料性能的影响

研究新型炭黑CD2109对NR/BR胶料性能的影响.结果表明,炭黑CD2109与橡胶间的相互作用较强;与填充普通炭黑的胶料相比,填充炭黑CD2109的胶料定伸应力和拉伸强度均增大,耐磨性能和耐热氧老化性能明显提高,具有更好的抗湿滑性能和较低的滚动阻力,综合性能较好.     

Incorporation of magnetic nanoparticles into lamellar polystyrene-b-poly(n-butyl methacrylate) diblock copolymer films: Influence of the chain end-groups on nanostructuration

In this article, we present new samples of lamellar magnetic nanocomposites based on the self-assembly of a polystyrene-b-poly(n-butyl methacrylate) diblock copolymer synthesized by atom transfer radical polymerization. The polymer films were loaded with magnetic iron oxide nanoparticles covered with polystyrene chains grown by surface initiated-ATRP. The nanostructuration of the pure and magnetically loaded copolymer films on silicon was studied by atomic force microscopy, ellipsometry, neutron reflectivity and contact angle measurement. The present study highlights the strong influence of the copolymer extremity - driven itself by the choice of the ATRP chemical route - on the order of the repetition sequences of the blocks in the multi-lamellar films. In addition, a narrower distribution of the nanoparticles’ sizes was examined as a control parameter of the SI-ATRP reaction.     

Al2O3/SiO2比和煅烧温度对煤系高岭土物理性能与显微结构的影响

以内蒙产的煤系高岭土为原料,通过添加α-Al2O3和SiO2细粉,以羧甲基纤维素为结合剂,在1450℃、1500℃、1550℃、1600℃的煅烧温度下制备了不同Al2O3/SiO2(Al/Si)比的试样.对试样的体积密度、显气孔率、耐压强度、线变化率等物理性能进行了检测.采用SEM与EDS分析,研究了试样的显微结构.研究表明:随着煤系高岭土中Al2O3/SiO2比从0.856增加到4.5,试样的体积密度从2.55下降到2.14 g/cm3,气孔率从5％增加到30％,耐压强度从20 MPa增加到50 MPa,体积变化从-17％增加到7％.当Al2O3/SiO2比为2.6时,试样经过1500℃×3h后,可以生成大量的柱状莫来石,具有良好的物理性能,可以作为一种有用的Al2O3-SiO2系低蠕变耐火材料.     

Influence of Serum and Hypoxia on Incorporation of [14C]-d-Glucose or [14C]-l-Glutamine into Lipids and Lactate in Murine Glioblastoma Cells

Glucose and glutamine are essential energy metabolites for brain tumor growth and survival under both normoxic and hypoxic conditions. Both metabolites can contribute their carbons to lipid biosynthesis. We used uniformly labeled [¹⁴C]‐U‐d ‐glucose and [¹⁴C]‐U‐l ‐glutamine to examine the profile of de novo lipid biosynthesis in the VM‐M3 murine glioblastoma cells. The major lipids synthesized included phosphatidylcholine (PtdCho), phosphatidylethanolamine (EtnGpl), phosphatidylinositol (PtdIns), phosphatidylserine (PtdSer), sphingomyelin (CerP Cho), bis(monoacylglycero)phosphate (BMP)/phosphatidic acid (PtdOH), cholesterol (C), cardiolipin (Ptd₂Gro), and gangliosides. Endogenous lipid synthesis, using either glucose or glutamine, was greater in media without fetal bovine serum (FBS) than in media containing 10 % FBS under normoxia. De novo lipid synthesis was greater using glucose carbons than glutamine carbons under normoxia. The reverse was observed for most lipids under hypoxia suggesting an attenuation of glucose entering the TCA cycle. Lactate was produced largely from glucose carbons with minimal lactate derived from glutamine under either normoxia or hypoxia. Accumulation of triacylglycerols (TAG), containing mostly saturated and mono‐unsaturated fatty acids, was observed under hypoxia using carbons from either glucose or glutamine. The data show that the incorporation of labeled glucose and glutamine into most synthesized lipids was dependent on the type of growth environment, and that the VM‐M3 glioblastoma cells could acquire lipids, especially cholesterol, from the external environment for growth and proliferation.     

Molecular Subtyping of Invasive Breast Cancer Using a PAM50-Based Multigene Expression Test-Comparison with Molecular-Like Subtyping by Tumor Grade/Immunohistochemistry and Influence on Oncologist’s Decision on Systemic Therapy in a Real-World Setting

In intermediate risk hormone receptor (HR) positive, HER2 negative breast cancer (BC), the decision regarding adjuvant chemotherapy might be facilitated by multigene expression tests. In all, 142 intermediate risk BCs were investigated using the PAM50-based multigene expression test Prosigna® in a prospective multicentric study. In 119/142 cases, Prosigna® molecular subtyping was compared with local and two central (C1 and C6) molecular-like subtypes relying on both immunohistochemistry (IHC; HRs, HER2, Ki-67) and IHC + tumor grade (IHC+G) subtyping. According to local IHC, 35.4% were Luminal A-like and 64.6% Luminal B-like subtypes (local IHC+G subtype: 31.9% Luminal A-like; 68.1% Luminal B-like). In contrast to local and C1 subtyping, C6 classified >2/3 of cases as Luminal A-like. Pairwise agreement between Prosigna® subtyping and molecular-like subtypes was fair to moderate depending on molecular-like subtyping method and center. The best agreement was observed between Prosigna® (53.8% Luminal A; 44.5% Luminal B) and C1 surrogate subtyping (Cohen’s kappa = 0.455). Adjuvant chemotherapy was suggested to 44.2% and 88.6% of Prosigna® Luminal A and Luminal B cases, respectively. Out of all Luminal A-like cases (locally IHC/IHC+G subtyping), adjuvant chemotherapy was recommended if Prosigna® testing classified as Prosigna® Luminal A at high / intermediate risk or upgraded to Prosigna® Luminal B.